Bleeding
Conditions
Brief summary
The objective of this study is to determine the dose response relationship regarding blood loss, PK, PD and clinical outcomes of MDCO-2010 in comparison to placebo and tranexamic acid in patients undergoing primary cardiac surgery with cardiopulmonary bypass. The aim of the study is to define minimally effective dose of MDCO-2010.
Detailed description
This was a two-stage, double-blind, randomized, parallel-group, multicenter Phase II dose-selection study to compare antifibrinolytic MDCO-2010 vs tranexamic acid and placebo in reducing blood loss. This study was designed to examine a broad range of doses to fully characterize the dose-response relationship between MDCO-2010 dose, plasma PK, PD, and clinical effects. In Stage 1, 90 patients were to be enrolled into one of six treatment groups with 15 patients per group: four groups were to receive MDCO-2010, one group was to receive tranexamic acid, and one group was to receive placebo. Stage 2 was to be an expansion of Stage 1. The study was terminated after 49 patients were enrolled into Stage 1.
Interventions
DRUGMDCO 1
MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 1: load 15 μg/kg; infusion 30 μg/kg/h; CPB prime 0.11 μg/mL priming volume
DRUGMDCO 2
MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 2: load 30 μg/kg; infusion 60 μg/kg/h; CPB prime 0.22 μg/mL priming volume
DRUGMDCO 3
MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 3: load 60 μg/kg ; infusion 120 μg/kg/h; CPB prime 0.44 μg/mL priming volume
DRUGMDCO 4
MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 4: load 90 μg/kg; infusion 180 μg/kg/h; CPB prime 0.65 μg/mL priming volume
DRUGTranexamic Acid
Tranexamic acid will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with tranexamic acid. The flow rates will be the same as for MDCO-2010.
DRUGSaline
A loading dose of saline will be followed by a continuous infusion of saline until sternal closure. In addition, the CPB reservoir will be primed with saline. The flow rates will be the same as for MDCO-2010.
Sponsors
The Medicines Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* For Stage 1: Planned primary isolated CABG surgery * For Stage 2: Planned primary isolated CABG surgery, OR Planned primary combined CABG and aortic valve replacement surgery * Men, aged 18 to 85 years, or Women, aged 18 to 85 years, either of postmenopausal status, defined as ≥1 year since last menstrual period AND if less than 65 years old with a negative pre-operative pregnancy test within 24 hours of surgery OR with medical history of hysterectomy or bilateral oophorectomy * Written informed consent
Exclusion criteria
* Off-pump surgery or hybrid procedures * Patients undergoing repeat sternotomy * Planned deep hypothermic circulatory arrest (\<28°C) * Known allergy, sensitivity, or contraindications to tranexamic acid * Epileptiform disorders, history of seizure activity, or anticonvulsive medication * Administration of clopidogrel, ticagrelor or ticlopidine within 5 days prior to surgery or prasugrel within 7 days prior to surgery. * Administration of low molecular weight heparin, glycoprotein IIb/IIIa inhibitors, or fondaparinux within 12 hours prior to surgery * Known history of coronary stent thrombosis within the last three months * History of stroke or transient ischemic attack within 3 months prior to surgery * History of deep venous thrombosis or pulmonary embolism * LVEF ≤35% or Grade III or IV * Body mass index \<20 or \>35 * Known active gastrointestinal (GI) or other non-catheterization bleeding within 7 days prior to surgery * Preoperative coagulation abnormalities defined as: * Platelet count \<100,000/L or \>350,000/L, or * International normalized ration (INR) \>1.5, or * Hematocrit \<36%, or * aPTT \>1.5 x ULN * Major surgical procedures within 30 days prior to surgery * Patient inability or refusal to receive donor blood products if necessary * Creatinine \>2 mg/dL or estimated glomerular filtration rate (eGFR) (calculated using Modification of Diet in Renal Disease \[MDRD\] equation \<30 mL/min) * Known heparin-induced thrombocytopenia type II * Known history of thrombophilia, such as AT-III, Protein C or Protein S deficiency, Factor V Leiden, anti-phospholipid syndrome * Active liver disease defined as any known current infectious, neoplastic or metabolic pathology of the liver OR ALT or AST elevation \>2x ULN or total bilirubin elevation \>1.5x ULN at Screening * Any condition requiring ongoing chronic immunosuppressive medication * Malignancy within 5 years prior to surgery * Receipt of an investigational drug or device within 60 days prior to surgery Any other condition which, in the opinion of the Principal Investigator, would put the subject at increased risk from participating in the study or otherwise prevent a patients participation in the study
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Chest Tube Drainage at 12 Hours After Surgery | 12 hours post CABG |
Countries
Germany, Switzerland
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MDCO 1 MDCO-2010 Dose 1: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 1: load 15 μg/kg; infusion 30 μg/kg/h; CPB prime 0.11 μg/mL priming volume | 8 |
| MDCO 2 MDCO-2010 Dose 2: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 2: load 30 μg/kg; infusion 60 μg/kg/h; CPB prime 0.22 μg/mL priming volume | 10 |
| MDCO 3 MDCO-2010 Dose 3: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 3: load 60 μg/kg ; infusion 120 μg/kg/h; CPB prime 0.44 μg/mL priming volume | 8 |
| MDCO 4 MDCO-2010 Dose 4: MDCO-2010 will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with MDCO-2010. MDCO 4: load 90 μg/kg; infusion 180 μg/kg/h; CPB prime 0.65 μg/mL priming volume | 10 |
| Saline Tranexamic Acid: Tranexamic acid will be administered as a loading dose followed by a continuous infusion until sternal closure. In addition, the CPB reservoir will be primed with tranexamic acid. The flow rates will be the same as for MDCO-2010. | 6 |
| Tranexamic Acid saline: A loading dose of saline will be followed by a continuous infusion of saline until sternal closure. In addition, the CPB reservoir will be primed with saline. The flow rates will be the same as for MDCO-2010. | 7 |
| Total | 49 |
Baseline characteristics
| Characteristic | MDCO 1 | MDCO 2 | MDCO 3 | MDCO 4 | Saline | Tranexamic Acid | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 71 years | 70 years | 66 years | 73 years | 66 years | 58 years | 69 years |
| Region of Enrollment Germany | 6 participants | 7 participants | 5 participants | 7 participants | 4 participants | 4 participants | 33 participants |
| Region of Enrollment Switzerland | 2 participants | 3 participants | 3 participants | 3 participants | 2 participants | 3 participants | 16 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 0 Participants | 8 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 7 Participants | 8 Participants | 4 Participants | 7 Participants | 41 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 7 | 7 / 8 | 4 / 7 | 7 / 10 | 5 / 6 | 4 / 6 |
| serious Total, serious adverse events | 2 / 7 | 2 / 8 | 1 / 7 | 2 / 10 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Chest Tube Drainage at 12 Hours After Surgery
Time frame: 12 hours post CABG
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MDCO 1 | Chest Tube Drainage at 12 Hours After Surgery | 600 mL |
| MDCO 2 | Chest Tube Drainage at 12 Hours After Surgery | 580 mL |
| MDCO 3 | Chest Tube Drainage at 12 Hours After Surgery | 480 mL |
| MDCO 4 | Chest Tube Drainage at 12 Hours After Surgery | 453 mL |
| Saline | Chest Tube Drainage at 12 Hours After Surgery | 645 mL |
| Tranexamic Acid | Chest Tube Drainage at 12 Hours After Surgery | 593 mL |